Shanu Modi, MD, on Clinical Implications of New Findings on T-DXd for Metastatic Breast Cancer

The DESTINY-Breast04 study is a really important study for breast cancer. We typically think of breast cancer in a very binary fashion where HER2 positive breast cancers are treatable with HER2 targeted therapies. HER2 negative breast cancers traditionally have not been. But we know there is a subgroup within this HER2 negative population where there is some expression of the HER2 receptor. There's low level of expression and we have not been able to target it with our currently available HER2 targeted therapies. And so we've typically had to treat these HER2 low patients as we treat HER2 negative patients. And typically, once these patients have exhausted lines of endocrine therapy and targeted therapies, we are left with offering sort of suboptimal, single agent palliative chemotherapy. So we really need, I think, more effective therapies for this population of patients. And so trastuzumab deruxtecan is a new generation HER2 antibody drug conjugate. And it has some very unique properties. In particular, it has a bystander effect, which allows it to be very active in cancers that have varying levels of HER2 expression, including HER2 low breast cancer. And in our own phase one study, we did show just that. In a population of more advanced HER2 low breast cancer patients, we saw very promising activity for trastuzumab deruxtecan. And that is really what led us today to the DESTINY 4 trial, which is the first randomized phase three study looking at trastuzumab deruxtecan, comparing it to standard chemotherapy then for patients with HER2 low metastatic breast cancer. We focused on enrolling patients with HER2 low metastatic breast cancer. And we define that as HER2 IHC scores of 1+ or 2+ without gene amplification. Patients on this trial had to have had one or two prior lines of chemotherapy in the advanced stage study. And endocrine or hormone-positive patients had to be considered endocrine refractory and having at least one line of endocrine therapy. And so this group of patients was then randomized, and in a two to one fashion the larger pool was randomized to trastuzumab deruxtecan, and we delivered that in the approved schedule and dose, which is IV every three weeks. And then the standard group, it was physician's choice to offer them one of a number of chemotherapy options. And the primary goal of the study really was to define the progression-free survival in the patients who have hormone positive HER2 low breast cancer initially. But then using hierarchical testing, we went on to look at the PFS for all patients on trial, and then importantly, overall survival for the hormone positive and all patients on study. In terms of the overall safe efficacy, ultimately, we found that patients who were randomized to the trastuzumab deruxtecan arm had significant improvement in progression-free survival. We found a hazard ratio of 0.5, and this is for the overall, the full study population, a very significant hazard ratio of 0.5 and an improvement in their median survival from approximately five months up to approximately 10 months. So a doubling of the time for the cancers to progress, which is really significant and clinically meaningful. The overall survival, likewise, was very positive, statistically positive. The hazard ratio for the full population was 0.64. And this led to an improvement in median survival from roughly 16 or 17 months up to 24 months with T-DXd. So again, an improvement in survival of over six months. And I mean, these are really compelling efficacy findings. We don't often see survival advantage in our late setting, in the advanced metastatic breast cancer setting. So these are very important I think efficacy findings for this new HER2 targeted therapy. In terms of safety, I mean, overall, we have been using trastuzumab deruxtecan in already the HER2 positive population, so we have a lot of familiarity. And we didn't see any new safety signals in the HER2 low population. I think lung toxicity is a well-acknowledged toxicity of T-DXd, and we did see approximately 12% of patients on this trial have lung toxicity. The majority were low-grade events and reversible, but there were a few cases of grade-five events, three total cases, for an incidence of 0.8% grade-five events. So I think it's a reminder for all of us that this is an important toxicity of this drug that warrants close monitoring and really prompt intervention to decrease potential high-grade events. So overall, I mean, I think this is a really positive result. It's exciting. We've been able to establish number one, the HER2 low population as a targetable population within breast cancer and have established trastuzumab deruxtecan as a new standard of care for this setting. And I mean, I think there's a lot of exciting opportunities that emanate from this work, and so a lot more promising things to look forward to.